The present invention relates in general to reversible gel compounds in which gelation is the result of response to a plurality of environmental stimuli. More particularly, the present invention is directed to polymeric solutions which gel in response to exposure to a critical minimum value of at least two environmental stimuli, such as in vivo stimuli found in human or other mammalian bodies. The gelation response can be reversed by reducing the value of at least one of such environmental stimuli to less than (or outside the range of) the critical minimum value.
The use of reversible gelling compounds is well known in the art. In the context of this art, xe2x80x9cgelxe2x80x9d means a form of material between the liquid and solid state that consists of physically crosslinked networks of long polymer molecules with liquid molecules trapped within the networkxe2x80x94a three-dimensional network swollen by a solvent. If the solvent is water, the gel is termed a xe2x80x9chydrogelxe2x80x9d.
Gels may be classified as either a chemical gel or a physical gel. The former are formed by chemical covalent bonds, resulting in a product called covalently cross-linked gels, and are not reversible. The latter are formed by secondary physical forces, such as hydrogen bonding or hydrophobic or charge interactions, and are reversible. Commercially available block copolymers of poly(ethylene oxide-b-propylene oxide-b-ethylene oxide) (PEO/PPO/PEO; Pluronics (BASF, Mount Olive, N.J.) or Poloxamers (ICI) are the best known examples of reversible, thermally gelling polymers. PEO/PPO/PEO copolymers are a family of more than 30 different nonionic surfactants, covering a wide range of liquids, solids and pastes with molecular weights ranging from about 1000 to 14,000. Concentrated solutions of PEO/PPO/PEO copolymers form reversible gels at high temperatures and revert to liquid state upon lowering of temperature. Gelation temperature depends on polymer composition and solution concentration.
Aqueous solutions of PEO/PPO/PEO copolymers demonstrate phase transitions from sol to gel (low temperature sol-gel boundary) and gel to sol (high temperature gel-sol boundary) with monotonically increasing temperature when the polymer concentration is above a minimum critical value. The mechanism of gelation of PEO/PPO/PEO copolymers is still uncertain.
Thermoreversible gels are also formed by several naturally occurring polymers such as gelatin (a protein prepared from partial hydrolysis of collagen), polysaccharides such as agarose, amylopectin, carrageenans, Gellan(trademark), and the like. All of this class of biopolymers form hydrogels when cooled. By contrast, cellulose derivatives gel by a different mechanism: they are sols at low temperatures and become gels at high temperatures. The sol-gel transition temperature is affected by substitutions at the hydroxyl group of cellulose.
Novel biodegradable triblock copolymers of polyethylene glycol and poly(lactic/glycolic acid)(PEG/PLGA/PEG) were developed, and as aqueous solutions exhibit sol to gel transition at body temperature. A nonresorbable thermoreversible gel based on copolymers of N-isopropylacrylamide with acrylic acid (poly(NiPAAm-co-AAc)) have been developed, and demonstrate reversible sol-to-gel transition at physiological temperature ranges due to lower critical solution temperatures exhibited by polymers of the N-isopropylacrylamide.
As an example of a different gelling mechanism, charged, water soluble polymers may form reversible gels in response to pH change in solution. For example, chitosan solutions exhibit a sol-to-gel transition at a pH of about 7.0, when pH changes from slightly acidic to neutral. The pH-triggered transition is slower than the transition caused by changes in temperature.
Chemically cross-linked gels are used extensively as matrices in chromatography and electrophoreses analytical methods to separate molecules according to molecular weight and charge. Additionally, efforts have been made to deliver drugs to human patients via reversibly gelling polymers, as well as topical applications and for ophthalmic delivery of therapeutic agents. It is known to use copolymer polyols which are available commercially under the trade name Pluronic(trademark), as described in U.S. Pat. No. 4,188,373.
In-situ gelling compounds have been proposed for use in implantation of drug delivery systems (for example, in cancer treatment), as well as injectable matrices for tissue engineering. Stimulus induced in-vivo gelation is a process that produces no toxic polymerization residues and results in no heat generation.
For example, U.S. Pat. No. 5,252,318 discloses a reversibly gelling aqueous composition that undergoes significant viscosity changes to simultaneous changes in both temperature and pH. The ""318 composition is comprised of a combination of at least two separate and distinct reversibly gelling polymers-one of which is temperature sensitive (such as methyl cellulose or block copolymers of polyoxyethylene and polyoxypropylene) and the other being pH sensitive (such as a polyacrylic acid). The composition is intended for use as drop instillable, oral and injectable drug delivery vehicles, and for topically applied lubricants, wetting agents and cleaning agents.
Other approaches to injectable polymers have included single-stimulus polymers, as for example in U.S. Pat. No. 5,939,485. Gelation of the aqueous polymer solution is responsive to a change in a single environmental stimulus, such as temperature, pH or ionic strength.
U.S. Pat. No. 4,732,930 discloses a chemically cross-linked gel composition comprised of a polymerized product that is obtained by polymerization of isopropylacrylamide monomer, a source of metal ions, a crosslinking agent and a liquid medium. The product exhibits a reversible phase transition function that results in a drastic volume change in response to changes of the liquid medium composition temperature or ion concentration.
U.S. Pat. No. 5,525,334 discloses a method for vascular embolization by introduction of an aqueous solution of a thermosensitive polymer which gels in vivo at the body temperature of a patient. Obviously, such a thermosensitive gelling response will be inoperative in a process wherein the polymer must travel a substantial distance within the patient""s body prior to gelation (such as when the gel is introduced through a catheter running from the femoral artery to the brain).
PCT published application number WO 99/56783 discloses a hydrogel for the treatment of aneurysms, whereby the gel carries both a radiopaque agent (permitting the radiogel to be visualized under fluoroscopy) and a therapeutic agent. The hydrogel is delivered through a catheter into an aneurysm, where the hydrogel becomes more viscous upon reaching body temperature or upon exposure to bodily fluids. The gelled compound blocks flow into the aneurysm, and can be adapted to deliver a human growth factor to promote growth of a cellular layer across the neck of the aneurysm.
It is therefore an object of the present invention to provide a single injectable aqueous gelling solution that is sensitive to at least two environmental stimuli, and more preferably, a compound that is sensitive to at least two in vivo environmental stimuli in a human or other mammalian body. The compound of the present invention will gel when exposed to critical minimum values of the environmental stimuli and is preferably a reversibly gelling compound, such that when the critical minimum values of all (or at a minimum, at least one) of the environmental stimuli fall below or outside the range of sensitivity, the gelled compound returns to an un-gelled condition.
The ideal multiple stimulus reversible hydrogel comprises an aqueous-based solution or compound having low viscosity at formation conditions, but exhibits rapid gelation at physiological conditions. It gels in response to multiple in-situ environmental stimuli, and is reversible. It must have reasonable mechanical strength and have biocompatibility with the host tissue.
The following references disclose processes or compounds useful in this art:
T. G. Park and A. S. Hoffman, xe2x80x9cSynthesis, Characterization, and Application of pH/Temperature-sensitive Hydrogelsxe2x80x9d, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 17 (1990), pp 112-113.
G. Chen and A. S. Hoffman, xe2x80x9cGraft Copolymers That Exhibit Termperature-induced Phase Transitions Over a Wide Range of pHxe2x80x9d, Vol 3, Nature, 1995, pp. 49-52.
S. Beltran, J. P. Baker, H. H. Hooper, H. W. Blanch and J. M. Prausnitz, xe2x80x9cSwelling Equilibria for Weakly Ionizable, Temperature-Sensitive Hydrogelsxe2x80x9d,Proc. Amer. Chem. Soc., 1991.
J. Zhang and N. A. Peppas, xe2x80x9cSynthesis and Characterization of pH- and Temperature-Sensitive Poly(Methacrylic acid)/Poly(N-isopropylacrylamide) Interpenetrating Polymeric Networks, Macromolecules, 2000 (currently available on-line on the world wide web).
T. G. Park, xe2x80x9cTemperature Modulated Protein Release From pH/Temperature Sensitive Hydrogels; Biomaterials 20 (1999), pp. 517-521.
The present invention comprises an aqueous polymeric solution capable of gelling upon exposure to a critical minimum value of a plurality of environmental stimuli. A xe2x80x9cpluralityxe2x80x9d of environmental stimuli may be any number equal to or greater than two, although in most cases the process of the present invention will utilize two stimuli. The aqueous polymeric solution is capable of having gelation reversed if all, or at a minimum, at least one, of the environmental stimuli fall below (or outside a range of) critical minimum values. The environmental stimuli may be any stimulus that induces gelation, and is exemplified by temperature, pH, ionic strength, electrical field, magnetic field, solvent composition, chemical composition, light, pressure and the like. The critical minimum values for each of these stimuli may vary depending upon the local environment in which the gel is used, and will likely be markedly different between medical (or, in vivo) and industrial uses.
In vivo environmental stimuli may be either associated with human patients, or in veterinarian use with domestic or farm animals. For example, the product and process of the present invention may be used with cattle, horses, sheep, pigs, dogs, cats, and the like. The environmental stimuli may be either conditions that are naturally found within the area of use (e.g. xe2x80x9cambientxe2x80x9d), or they may be externally imposed. Generally speaking, when injected into a human, the aqueous polymeric solution of the present invention is injected into a specific locus within the bodyxe2x80x94either a cavity (such as a post-operative tumor site) or a conduit/duct (such as a blood vessel) or into a tissue mass (such as a tumor).
The polymeric solution may either be a carrier for a pharmaceutically active therapeutic agent (in which case it will typically be an aqueous solution), or it may merely act as an inert blocking mass. An example of the former is the injection of chemicals or radioisotopes delivered through a catheter to a tumor mass; an example of the latter is injection of a gelled mass into a tubular body so as to cause a restriction therein (e.g. an aneurism of a blood vessel or the vas deferens for purposes of reversible sterilization in males). Likewise, the polymeric solution may be used in industrial situations wherein it may not be an aqueous solution.
It would be of great medical benefit in in vivo environments, if an aqueous polymeric solution could be transported in a catheter within the body for extended distances without gelation. For example, if it is desired to implant a quantity of radioisotope in a gelled mass within the brain, a catheter may be inserted into the patients femoral artery and the therapeutic agent is transported from that locale to the brain. Through use of the process of the present invention, for example, the two stimuli to induce gelation may be temperature and pH in the blood stream, such that warming of the liquid polymeric compound alone (within the catheter) will not cause gelation. It is not until the compound contacts the blood in the brain, and is induced by the pH or ionic strength of the blood to gel, that gelation occurs.